Galanin receptors (GalRs) are G-protein-coupled receptors (GPCRs) that mediate signaling of galanin and other neuropeptides in the galanin family. So far, three subtypes of GalRs have been identified, namely GalR1, GalR2 and GalR3. With relatively low sequence similarity between one and other. However, their sequences are highly conserved among different vertebrate species.
Widely expressed in the brain and peripheral tissues, GalRs are involved in the regulation of a number of biological functions, including nociception, cognition, mood control, neuroendocrine function, reproduction, feeding control, energy and osmotic homeostasis, and metabolism. They have also been implicated in many human diseases, including neurological and metabolic disorders, inflammation, and cancers. However, understanding the roles of GalRs in health and disease, and clinical translation have been hindered by the lack of metabolically stable and receptor-specific probes.
Spexin (SPX) is a newly identified, GalR-cognate neuropeptide. Expressed centrally and peripherally, SPX can regulate gastrointestinal motility, adrenocortical cell proliferation, cardiovascular and renal function, nociception, reproduction, and feeding. It has also been implicated in a number of human disorders, including obesity, type-II diabetes, nonalcoholic fatty liver disease, and constipation.
Containing 14 amino acids and amidated at C-terminal, SPX is similar to the N-terminal sequence of galanin. Nevertheless, receptor recognition profiles of these two neuropeptides are different: galanin activates GalR1, GalR2 and GalR3. Whereas, SPX only activates GalR2 and GalR3. For GalR2, SPX and galanin have comparable activity; while for GalR3, SPX has much better activity than galanin.
Elucidating the biological role of GalRs in health and disease, and clinical translation of this knowledge to new methods of medical treatment has been hindered by the lack of metabolically stable and receptor-specific probes. Thus, there is a need to develop new agonists receptor selective probes of GalR2 and GalR3 with improved metabolic properties.